1
Appendix 1. Literature Search Strategy
2
Among the Medical Subject Headings (MeSH) searched were estrogens, conjugated; conjugated
3
equine estrogen; Premarin; estradiol; Vagifem; Estring; Estrace; estriol; estrogen replacement
4
therapy; atrophy; vaginal diseases; atrophic vaginitis; vaginal discharge; dysuria; urinary
5
incontinence; overactive bladder; sexual dysfunction; dyspareunia; randomized controlled trial;
6
controlled clinical trial; comparative study; prospective study; cross-over study; meta-analysis;
7
and systematic review. We did not attempt to identify unpublished articles or abstracts, and we
8
did not contact study authors. The search was limited to human subjects and English language.
9
Reference lists of selected articles and review papers were screened for additional eligible
10
references.
11
12
Rahn DD, Carberry C, Sanses TV, Mamik MM, Ward RM, Meriwether KV, et al. Vaginal estrogen for genitourinary syndrome
of menopause: a systematic review. Obstet Gynecol 2014;124.
The authors provided this information as a supplement to their article.
© Copyright 2014 American College of Obstetricians and Gynecologists.
Page 1 of 4
13
Appendix 2. Non–Placebo-Controlled Studies of Vaginal Estrogen in Women With
14
Genitourinary Syndrome of Menopause
Study Author,
Country, y
Study
Quality
Intervention (n)
Comparator (n)
Conjugated estrogen cream⁺ 1 g
Daily 21 d, then none 7 d (63)
Conjugated estrogen cream 2 g
3x per wk (67)
Conjugated estrogen cream 2 g
3x per wk (67)
Estriol 0.5 mg cream
Daily 2 wk, then 3x per wk (82)
Estriol 1 mg ovule
Daily 2 wk, then 2 ovules 1x per
wk (103)
OCP vaginally 1x per wk (20)
Ayton,(31) Australia,
1996
A
Estradiol vaginal ring, once
(131)
Bachmann,(32) USA,
1997
Nachtigall,(33) USA,
1995*
Barentsen,(34) The
Netherlands, 1997
Capobianco,(35)
Italy, 2012
B
Estradiol vaginal ring, once
(129)
Estradiol vaginal ring, once
(129)
Estradiol vaginal ring, once (83)
*
A
A
Chompootaweep,(36)
Thailand, 1998
B
Dickerson,(37) USA,
1979
Dugal,(38) Norway,
2000
Henriksson,(39)
Sweden, 1994
Kicovic,(40) Italy,
1980
B
A
A
C
Estriol 1 mg ovule
Daily 2 wk, then 2 ovules 1x per
wk plus PFMT (103)
Conjugated estrogen cream 1 g
3x per wk for 1 wk, then 2x per
wk for 1 wk, then 1x per wk for
6 wk (20)
Estradiol 0.01% cream 0.2 mg
Daily 2 wk (20)
Estradiol vaginal tablet 25 μg
Daily 2 wk, then 2x per wk (46)
Estradiol vaginal ring, once
(112)
Estriol cream 1 mg
Daily 3 wk, then 2x per wk (23)
Lose,(41) Denmark,
2000
B
Estradiol vaginal ring
Every 12 wk (134)
Manonai,(42)
Thailand, 2001
Mattson,(43) Sweden,
1983
Mattson,(44) Sweden,
1989
Mettler,(45)
Germany, 1991
B
Estradiol vaginal tablet 25 μg
Daily 2 wk, then 2x per wk (27)
Estriol cream 0.5 mg
Daily 2 wk, then 2x per wk (15)
Estradiol vaginal tablet 25 μg
Daily 3 wk, then 2x per wk (20)
Estradiol vaginal tablet 25 μg
Daily 2 wk, then 1x per wk (17)
B
C
C
Conjugated estrogen cream 2 g
Daily 2 wk (10)
Estriol vagitory 0.5 mg
Daily 2 wk, then 2x per wk (46)
Estriol pessary 0.5 mg
Daily 3 wk, then 2x per wk (53)
Estriol cream 0.5 mg (30) or
Estriol suppository 0.5 mg (21)
Daily 3 wk, then 2x per wk
Estriol pessary 0.5 mg
Daily 3 wk, then every other day
(117)
Conjugated estrogen cream 1 g
Daily 2 wk, then 2x per wk (63)
Estriol suppository 0.5 mg
Daily 2 wk, then 2x per wk (15)
Estradiol vaginal tablet 50 μg
Daily 3 wk, then 2x per wk (20)
Estradiol vaginal tablet 25 μg
Daily 2 wk, then 2x per wk (34)
FollowUp
Duration
12 wk
12 wk
12 wk
12 wk
24 wk
8 wk
2 wk
24 wk
12 wk
16 wk
24 wk
12 wk
8 wk
9 wk
52 wk
Rahn DD, Carberry C, Sanses TV, Mamik MM, Ward RM, Meriwether KV, et al. Vaginal estrogen for genitourinary syndrome
of menopause: a systematic review. Obstet Gynecol 2014;124.
The authors provided this information as a supplement to their article.
© Copyright 2014 American College of Obstetricians and Gynecologists.
Page 2 of 4
Rioux,(46) Canada,
2000
Trevoux,(47) France,
1982
Weisberg,(48)
Australia, 2005
Antoniou,(49)
Greece, 1997
Botsis,(50) Greece,
1997
Gupta,(51) USA,
2008
Holmgren,(52)
Sweden, 1989
Long,(53, 54) China,
2006
Biglia,(55) Italy,
2010
A
Estradiol vaginal tablet 25 μg
Daily 2 wk, then 2x per wk (80)
Estriol cream 0.5 mg
Daily 3 wk, then 2x per wk (54)
Estradiol vaginal ring
Every 12 wk (126)
Estradiol vaginal ring every 12
wk and 100mg vaginal
progesterone suppository 7 d per
mo (28)
Conjugated estrogen cream 1 g
Frequency unspecified (36)
Estradiol vaginal ring, once (12)
C
Estradiol vaginal ring, once (11)
B
Conjugated estrogen oral tablet
0.625mg per day (27)
Estriol cream 0.25mg 2x per wk
(10) or estradiol vaginal tablet
12.5 μg 2x per wk (8)
Estradiol vaginal tablet 25 μg
Daily 2 wk, then 2x per wk (21)
Conjugated estrogen cream 2 g
Daily (15)
B
C
A
B
B
C
Ekin,(56) Turkey,
2011
Nachtigall,(57) USA,
1994
C
Parsons,(58) USA,
2003 and Kessel,(59)
USA, 2003†
Raghunandan,(60)
India, 2010#
Pinkerton,(61) USA,
2003
B
Conjugated estrogen cream 1 g
Daily 2 wk, then 2x per wk (46)
B
Conjugated estrogen cream 1 g
Daily 2 wk, then 2x per wk (25)
Estradiol vaginal ring every 12
wk and daily oral placebo (45)
Raz,(62) Israel, 2003
C
A
A
Estriol pessary 0.5 mg
2x per wk and daily oral placebo
(86)
Conjugated estrogen cream 2 g
Daily 21 d, then none 7 d (79)
Estriol suppository 0.5 mg
Daily 3 wk, then 2x per wk (28)
Estradiol vaginal tablet 25 μg
Daily 2 wk, then 2x per wk (59)
Transdermal estradiol 50 μg per
d and levonorgestrel-releasing
intrauterine device (28)
24 wk
Tibolone 2.5 mg orally
Daily (36)
Transdermal estradiol 14 μg per
d (12)
Vaginal estradiol ring
20-30 μg per d (11)
Conjugated estrogen cream 1 g
Daily (30)
Non-hormonal moisturizer
(Replens®) 2.5 g
2x per wk (8)
Hyaluronic acid 5 mg tablet
Daily (21)
Non-hormonal moisturizer
(Replens®)
3x per wk (15)
Non-hormonal moisturizer
(Replens®)
Daily 2 wk, then 2x per wk (47)
Nonhormonal KY lubricant gel
Daily 2 wk, then 2x per wk (25)
Estradiol vaginal ring every 12
wk and daily oral raloxifene 60
mg (46)
Vaginal pessary placebo
2x per wk and daily oral
nitrofurantoin macrocrystal 100
mg (85)
6 mo
8 wk
48 wk
52 wk
12 wk
12 wk
12 wk
12 wk
8 wk
12 wk
12 wk
12 wk
6 mo
9 mo
15
wk, week; PFMT, Pelvic Floor Muscle Therapy; OCP, oral contraceptive pill containing 250 μg
16
levonorgestrel plus 30 μg ethinyl estradiol.
Rahn DD, Carberry C, Sanses TV, Mamik MM, Ward RM, Meriwether KV, et al. Vaginal estrogen for genitourinary syndrome
of menopause: a systematic review. Obstet Gynecol 2014;124.
The authors provided this information as a supplement to their article.
© Copyright 2014 American College of Obstetricians and Gynecologists.
Page 3 of 4
17
⁺ Conjugated estrogen cream (Premarin) concentration in all studies involved: 0.625 mg per 1 g
18
cream.
19
*, Supplemental companion paper to Bachmann 1997.(32)
20
†
21
receiving conjugated estrogen or non-hormonal moisturizer creams were considered for this
22
review.
23
#
24
0.5 gm 2% testosterone (1 mg) cream; only the conjugated estrogen cream versus non-hormonal
25
lubricant gel comparison was considered for this review.
, Study also contains randomization to oral Raloxifene or placebo; only the oral placebo patients
, Study also contains a third comparison group receiving both conjugated estrogen cream and
Rahn DD, Carberry C, Sanses TV, Mamik MM, Ward RM, Meriwether KV, et al. Vaginal estrogen for genitourinary syndrome
of menopause: a systematic review. Obstet Gynecol 2014;124.
The authors provided this information as a supplement to their article.
© Copyright 2014 American College of Obstetricians and Gynecologists.
Page 4 of 4